This application claims benefit under 35 U.S.C. xc2xa7119 of application No. 19941540.4-44 filed on Sep. 1, 1999 and application No. 10027611.3 of Jun. 6, 2000 in Germany, which are hereby incorporated by reference.
The invention relates to sulfonylcarboxamide derivatives and their physiologically acceptable salts and physiologically functional derivatives and to their use for preparing medicines for the prevention and treatment of hyperlipidemia and arteriosclerotic disorders.
Sulfonylcarboxamides have already been described In Chemical Abstracts 96, 142393m (1982).
In DE 2145686, 2-chloro-5-sulfamylbenzoic acid derivatives have already been described as lipid-lowering agents.
The invention is based on the object of providing further compounds which have a therapeutically utilizable hypolipidemic action. In this context, the object was, in particular, also to provide compounds having an increased hypolipidemic action compared to the 2-chloro-5-sulfamylbenzoic acid derivatives from DE 2145686.
Accordingly, the invention relates to compounds of the formula I 
in which
X, R1, R2, R3 are, independently of one another, NR6R7, (CH2)-pyridyl, (CH2)n-phenyl, where n can be 0-6 and the phenyl radical can be substituted up to two times by F, Cl, Br, CF3, NH2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COO(C1-C6)-alkyl, COO(C3-C6)-cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2;
(C1-C8)-alkyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, morpholinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, it being possible for each of the rings to be substituted by phenyl, (C1-C6)-alkyl-phenyl, xe2x80x94OH, (C1-C8)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, (CO)-phenyl, where the phenyl substituent is unsubstituted or substituted up to two times by F, Cl, Br, OH, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, CONH(C3-C6)cycloalkyl, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, NHxe2x80x94CO-phenyl;
R6 and R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkylxe2x80x94OH, (C1-C6)-alkyl-NH2, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, (C1-C6)-alkyl-di-phenyl, (C1-C6)-alkyl-O-phenyl, CHO, CO-phenyl,
xe2x80x83(CH2)nxe2x80x94Ar, where n can be 0-6, and Ar can be equal to phenyl, biphenylyl, 1- or 2-naphthyl, 1- or 2-tetrahydrofuranyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 1-pyrazolyl, 3-, 4- or 5-isoxazolyl, (C3-C6)-cycloalkyl, piperidinyl, pyrrolidinyl, oxopyridyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4- or -5-yl and Ar can be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94CH2xe2x80x94O, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, CONH(C3-C6)cycloalkyl, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, NHxe2x80x94CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, (CH2)n-phenyl, Oxe2x80x94(CH2)n-phenyl, Sxe2x80x94(CH2)n-phenyl, SO2xe2x80x94(CH2)n-phenyl, where n=0-3;
and their physiologically acceptable salts.
Preference is given to compounds of the formula I in which one or more radical(s) is/are as defined below:
R1, R2 are, independently of one another, NR6R7, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridyl, it being possible for each of the rings to be substituted by phenyl, (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, (CO)-phenyl, where the phenyl substituent is unsubstituted or substituted up to two times by F, Cl, Br, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, S-(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)-alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, NHxe2x80x94CO-phenyl;
R6, R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2,
xe2x80x83(CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3- or 5-isoxazolyl, (C3-C6)-cycloalkyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl or indol-3-yl, indol-5-yl and Ar can be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, NH2, NHxe2x80x94CO-phenyl, (CH2)n-phenyl, Oxe2x80x94(CH2)n-phenyl, Sxe2x80x94(CH2)n-phenyl, where n=0-3;
X, R3 are, independently of one another, NR8R9, pyrrolidinyl, piperidinyl, morpholinyl, (C1-C8)-alkyl, (CH2)n-phenyl, where n=0-6 and the phenyl radical can be substituted up to two times by F, Cl, Br, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COO(C1-C6)-alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2;
R8, R9 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-COxe2x80x94(C1-C6)-alkyl, SO2-benzyl, SO2-benzyl-OCH3, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl or thienyl and Ar can be substituted up to two times by F, Cl, Br, CF3, NO2, CN, OCF3, Oxe2x80x94CH2xe2x80x94O, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, NHxe2x80x94CO-phenyl, (CH2)n-phenyl, Oxe2x80x94(CH2)n-phenyl, Sxe2x80x94(CH2)n-phenyl, SO2xe2x80x94(CH2)n-phenyl, where n=0-2;
and their physiologically acceptable salts.
Particular preference is given to compounds of the formula I in which one or more radical(s) is/are as defined below:
R1, R2 are, independently of one another, NR6R7, piperidinyl, piperazinyl, tetrahydropyridyl, it being possible for each of the rings to be substituted by phenyl, (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (CO)xe2x80x94(C1-C6)-alkyl;
R6, R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl, 2-, 3- or 4-pyridyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 4-morpholinyl and Ar can be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, COOH, NH2,(CH2)n-phenyl, where n can be 0-3;
X is NR8R9, piperazinyl, (C1-C6)-alkyl, (CH2)n-phenyl, where n can be 0-6;
R3 is NR10R11, piperazinyl;
R8, R9 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-COxe2x80x94(C1-C6)-alkyl, SO2-benzyl, SO2-benzyl-OCH3, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl or thienyl;
R10, R11 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-COxe2x80x94(C1-C6)-alkyl, SO2-benzyl, SO2-benzyl-OCH3, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl or thienyl;
and their physiologically acceptable salts.
Very particular preference is given to compounds of the formula I in which one or more radical(s) is/are as defined below:
R1, R2 are, independently of one another, NR6R7, piperidinyl, piperazinyl, tetrahydropyridyl, it being possible for each of the rings to be substituted by phenyl, (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (CO)xe2x80x94(C1-C6)-alkyl;
R6, R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl, 2-, 3- or 4-pyridyl, piperidinyl, pyrrolidinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 4-morpholinyl and Ar can be substituted up to two times by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, COOH, NH2, (CH2)n-phenyl, where n can be 0-3;
X is (C1-C6)-alkyl, (CH2)n-phenyl, where n can be 0-6;
R3 is NR10R11, piperazinyl;
R10, R11 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-COxe2x80x94(C1-C6)-alkyl, SO2-benzyl, SO2-benzyl-OCH3, (CH2)nxe2x80x94Ar, where n can be 0-6 and Ar can be equal to phenyl or thienyl;
and their physiologically acceptable salts.
The invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof. The alkyl, alkenyl and alkynyl radicals in the substituents X, R1, R2, R3, R6, R7, R8, R10 and R11 may be either straight-chain or branched.
Pharmaceutically acceptable salts are particularly suitable for medical applications because their solubility in water is higher than that of the initial or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of compounds of the formula I are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
Preference is given to the salts of methanesulfonic acid, toluenesulfonic acid, maleic acid and phosphoric acid.
Particular preference is given to the methanesulfonates of the compounds of the formula I.
The invention furthermore relates to physiologically functional derivatives of the compounds of the formula I. The term xe2x80x9cphysiologically functional derivativexe2x80x9d used herein refers to any physiologically tolerated derivative of a compound according to the invention, for example an ester, which is able on administration to a mammal, such as, for example, a human, to form (directly or indirectly) such a compound or an active metabolite thereof.
A further aspect of this invention is the use of prodrugs of the compounds of the formula I. Such prodrugs can be metabolized in vivo to a compound of the formula I. These prodrugs may themselves be active or not.
The compounds of the formula I may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the formula I lie within the scope of the invention and are a further aspect of the invention.
All references hereinafter to xe2x80x9ccompound(s) of formula (I)xe2x80x9d refer to compound(s) of the formula (I) as described above, and the salts, solvates and physiologically functional derivatives thereof as described herein.
The amount of a compound of formula (I) which is necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can most suitably be administered as infusion of from 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. It is thus possible for ampoules for injections to contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, to contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the salt of the compound of the formula (I). For the prophylaxis or therapy of the abovementioned conditions, the compounds of formula (I) themselves can be used as the compound, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not hazardous for the patient""s health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet which may contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including other compounds of formula (I). The pharmaceutical compositions according to the invention can be produced by one of the known pharmaceutical methods which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration although the most suitable mode of administration in each individual case depends on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated slow-release formulations also lie within the scope of the invention. Formulations resistant to acid and gastric fluid are preferred. Suitable coatings resistant to gastric fluid comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, lozenges or tablets, each of which contain a defined amount of the compound of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent and/or a (plurality of) surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions suitable for peroral (sublingual) administration comprise lozenges which contain a compound of formula (I) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabric.
Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient""s epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active ingredient can be released as described, for example, in Pharmaceutical Research, 2(6): 318 (1986) by electrotransport or iontophoresis.